Novobiocin in combination with high-dose chemotherapy for the treatment ofadvanced breast cancer: A phase 2 study

We conducted the first phase 2 and pharmacologic study to evaluate the comb ination of novobiocin (a coumeromycin antibiotic that has been shown to aug ment alkylating agent cytotoxicity in experimental models) and high-dose cy clophosphamide and thiotepa followed by autologous marrow support in women with chemosensitive advanced breast cancer. Its aims were (1) to determine progression-free survival (PFS) and overall survival (OS), (2) to evaluate the pharmacokinetics of cyclophosphamide and thiotepa, and (3) to measure t he ability of novobiocin to reverse alkylator drug resistance in vitro. For ty-one women with chemotherapy-responsive advanced breast cancer received c yclophosphamide (4 g/m(2)) for peripheral blood stem cell mobilization (tre atment 1) followed by high-dose cyclophosphamide (1.5 g/m(2) per day for 4 days), thiotepa (200 mg/m(2) per day for 4 days), and novobiocin (4 g/day o rally for 7 days) (treatment 2) and autologous marrow support. The median P FS was 10 months (range, 0.2-70.6 months) and OS, 21.5 months (range, 0.2-7 0.6 months). There was no statistically significant relationship between PF S or OS and area-under-the-curve values of cyclophosphamide, thiotepa, or 4 -hydroxycyclophosphamide. Patient plasma samples (n = 12) obtained during n ovobiocin therapy were able to reverse alkylator drug resistance in an in v itro colony-forming assay. Correlative laboratory studies in an in vitro mo del system demonstrated that patient plasma after novobiocin treatment resu lted in the magnitude of resistance reversal that had been predicted by pri or preclinical experiments. Clinically, however, this activity of novobioci n did not translate into a substantial increase in PFS or OS compared with historical controls treated with high-dose alkylator therapy alone.